17beta-(dihydroxypropanoyl)-substituted steroids



United States Patent() 3,033,747 175-(DIHYDROXYPROPANOYU-SUBSTITUTEDSTEROIDS v Ellis R. Pinson, Jr., Waterford, Eugene J. Agnello, Lyme,

Chas. Pfizer & Co., Inc., New York, N.Y., a corporation of Delaware v'No Drawing. Filed May 11, 1960, Ser. No. 28,180 3 Claims. (Cl. 167-65)This application is concerned with new and useful steroid compounds.More particularly it is concerned with certain steroids havingadrenocortical activity characterized by having unique chemical teaturesin the carbon atom side chain at the 17p-position. It is concerned alsowith a method of making these valuable compounds and with pharmaceuticalcompositions containing them together with pharmaceutically acceptableexcipients.

The essence of this invention is the discovery that adrenocorticallyactive steroids heretofore characterized by the presence of an a-hydroxyacetyl group at the 17p: position are also therapeutically useful whenthe. a-hy-f droxy acetyl group is replaced with -a dihydroirylatedpropanoyl group.

Adrenocortically active steroids now constitute avvwelldefined class inthe art, and include therapeutically active agents having a wide rangeof applications in the medical field. Cortisone, hydrocortisone,prednisone, predni solone, 2-methyl-prednisolone,6-rnethyl-predniso1one; 16- methyl-predn isolone,9a-fluoro-hydrocortisone and others have been found to be useful assystemic and topical anti l inflamatory agents and for other medicaluses. Theyhavefor example been used in the treatment of rheumatoiddiseases and allergies. They are pregnane derivatives having acyclopentanopolyhydrophenanthrene nucleus. They gen-- erally have adouble bond at the 4-position, a keto group 3 at the 3-position and anoxygen function at the I l-position. Certain 9,11-dihalopregnenederivatives have adrenocortical activity. The compounds within thepurview of this invention belong to the class of active steroids.

The compounds of this invention may be represented by the formula:

wherein R is a cyclopentanopolyhydrophenanthrene nucleus characterizedby having adrenocortical activity when;

adrenocortically 3,033,747 Patented May 8, 1962 group derived frommonoand dicarboirylic acids containing only carbon, hydrogen arid oxygenup to a total of ten carbon atoms and the alkali metal and alkalineearth I metal salts of the said dicarboxylie' acids, as well as acetalsand Gerald D. Laubach, Niantic, Conm, assignors to and ketals formed byreaction of both hydroxyl groups with the carbonyl function of loweralkyl 'aldehydes and ketones. This latter class of compounds may begenerically referred toas dioxolanes.

The preferred compounds within the purview of this invention includethose having the formulas:

cHa Q om-o /R1 l A ,CH-O Rs X. CHM

ornont 1110125 1 1 "-011 R4 2: ona R1 O:

and

In the above structures; X is hydrogen; halogen, inethoxy or ethoxy; Yis fl-hydroxyl' or keto; R is hydrogen or methyl; R is hydrogen,fluorine, chlorine or methyl; 3;;

whereinR is an acyl group; R and R are hydrogen or acyl, an .acyl groupwherever located containing only carbon, hydrogen and oxygen, beingderived from monoor dicarboxylic acids containing up to ten carbonatoms; and R and R which may be the same or difierent in a particularcompound are hydrogen or lower alkyl each containing up to four carbonatoms except that both Ri and R cannot'behydrogen in a particularcompound. In

the :preierred compounds represented above, the carbon atom at thesixteen position is always substituted with atleast one hydrogenandatleast three of R R R and the second substituent on the number sizgteencarbon atom will always be hydrogen. The water solubility of com poundsderived from tdicarboxylic acids is enhanced by conversion to alkalimetal or alkaline earth metal salts by reaction with a suitable basesuch 'asisodium carbonate or calcium hydroxide; These salts are includedwithin the purview of this invention.

Starting compounds which are useful in the preparation of the valuablecompounds of this invention include those.

having the formula:

- wherein has the same meaning as above andN, which is located at the HS-position, is a propenoyl group.

Starting compounds useful for the preparation of the preferred compoundsof this invention include those having structures identical withthe-ones shown above except that the substituent at the Uri-position isreplaced with a prq n grown A yp a starting mp is methylene-Apregnadiene-llfl,l7ct-diol-3, 20-dione, having the structure:

The starting materials are converted to the valuable The desired resultis best effected by reacting 1 equimolar portions of steroid andoxidizing agent in a lower ether solvent containing up to eight carbonatoms at a temperature of from about 20 to about 30 C. for a period offrom about sixteen to about seventy-two hours. An excess of osmiumtetroxide say, for example, up to about a 20% molar excess can be usedso as to insure complete reaction of the valuable steroid startingmaterial although this is not necessary. Illustrative solvents include,for example, dioxane, diethyl ether, tetrahydrofuran, dimethyl ethyleneglycol and other glycol ethers containing up to a total of eight carbonatoms. The preferred solvent is dioxane because of its good solubilitycharacteristics with respect to both steroid and oxidizing agents.Further, it is readily removed by evaporation.

During the course of the reaction, an intermediate osmate esterprecipitates and this is readily converted to a dihydroxy compound byknown methods. It is possible, for example, to decompose the ester bytreatment with various polyhydric compounds in alkaline solution, forexample, mannitol in aqueous potassium hydroxide. In a preferred method,the osmate ester is decomposed by treatment with hydrogen sulfide. Thisreagent decomposes the ester and precipitates the osmium as a sulfidewhich is readily removed by filtration. The best yields are obtained ifsuflicient hydrogen sulfide is bubbled into the reaction mixture so asto form a saturated solution. The desired product is readily recoveredfrom the filtrate by evaporation preferably in vacuo. It may be purifiedby recrystallization from a suitable solvent, for example, 1:1 ethylacetate-methanol.

It will be noted by reference to the formulas set forth above that it isspecifically intended to include within the purview of this inventionnot only compounds having free hydroxyl groups at the 16-position andthe a and ,B-positions of the propanoyl moiety, but also these samecompounds in which one or more of these groups is esterified with anacyl hydrocarbon group containing up to ten carbon atoms, that is, thegroup is an acylated hydroxyl group. Compounds of this nature arereadily prepared by standard methods well known in the art. They aremost simply prepared by mixing the reactants and allowing them to standtogether for a period of time at from 20 C. to 30 C. The duration of thereaction will depend upon the reactivity of the acylating agent and withsome acylating agents gentle heat may hasten reaction. Mostconveniently, the acylating agent is an anhydride and the duration ofthe reaction is from eight to twentyfour hours. Using an anhydride, thereaction is best carried out in the presence of a basic reagent,suitably m amine. Pyridine is especially convenient because it is aliquid with excellent solubility characteristics. Often the pyridine canserve notonly as the alkaline reagent but also as the solvent. Thus, theester is formed by dissolving the steroid and the anhydride in pyridineand allowing the mixture to stand for from about eight to abouttwenty-four hours. Of course, other solvents well known to those skilledin the art may be successfully employed.m y

Most often the acylated hydroxyl groups will be identical, but it ispossible to preparecompounds. within the purview of thisinventioninwhich the groups are dissimilar. For example, one can utilizea starting propenoyl compound in which the hydroxyl group at the sixteenposition is already acylated, and subsequently. acylate the two hydroxylgroups in the a and S -positions" in the propanoyl moiety with anotheracylating agent. Since the hydroxyl group at the a-position is asecondary hydroxyl group and the one in the fi-position is primary theymay be acylated, ,as is well known, independently of each other.

Free alcohols are formed from the corresponding esters by gentlehydrolysis, for example, with dilute hydrogen chloride in aqueousmethanol or with potassium carbonate in aqueous methanol. Since the rateat which esters formed from primary and secondary alcohols may behydrolyzed varies considerably, this hydrolysis reacsuch as starch ormilk sugar. Aqueous suspensions and tion may be utilized to formcompounds in which there are diverse acyl hydrocarbon groups at thevarious positions. I

The term acylated hydroxyl group include those groups derived from monoand dicarboxylic acids containing only carbon, hydrogen and oxygen up toa total of ten carbon atoms. In the event that the groupis de-' rivedfrom a dicarboxylic acid, it is often advantageous totreat atherapeutically active compound with a base derived from an alkali metalor alkaline earth metal to prepare a metal salt. These bases include,for example, sodium, potassium, barium and calcium hydroxide as well asthe corresponding carbonates'and bicarbonates. Products so prepared areespecially useful because of their increased solubility in Water. I

Those skilled in the art will recognize that the number 2-carbon atom,i.e., the a-carbon atom, in the propanoyl moiety is asymmetric and that,therefore, the compounds within the purview of this invention existasoptical isomers. It is intended to include both isomers within thepurview of the invention. It is possible to separate the isomers, forexample, by chromatography, but it is not I necessary to do so sinceboth are active. For most therapeutic purposes, therefore, it isimmaterial whether a pure optical isomer or a mixture is used.

If it is desired to separate the isomers this can be readilyaccomplished by paper chromatography according to means well known inthe art. For example, the free alcohols can be separated on paper usingchloroform as the mobile phase and formamide as the stationary phase.The esters can be separated using a 1:3 mixture of chloroform andbenzene as the mobile phase and formamide as the stationary phase. Eachproduct may be isolated by dissolving it from the -paper using asuitable solvent such as ethyl acetate or chloroform.

The biologically active compounds of this invention may be administeredalone or in combination with ac'-" ceptable pharmaceutical carriers, thechoice of which is determined by the preferred route of administration,the

practice.

ful to treat the types of pathological conditions often treated withhydrocortisone. Because of their great adrenocortical activity, it issometimes possible to use dosages of these compounds which are lowerthan those of hydrocortisone. a

For oral administration, the compounds may be administered in the formof tablets containing excipients elixirs which may be sweetened orflavored may also be used. To apply these therapeutic agents topically,they may be prepared in the form of ointments and salves in suitablebases especially non-aqueous petrolatum type bases. For intro-articularinjection aqueous suspensions may be employed.

1113,17u,21-trio1-3,20-dione, one of the compounds of this invention. Itexemplifies also the general method by.

which the compounds of this invention are prepared.

In this case various suspendingand' wetting agents may. be added to thecompositions to obtain a suspension not tending to settle out easily orto pack; lntramuscul a1 I and subcutaneous dosage forms may also beprepared by Theacetonides within the purview of this invention areprepared by procedures well known to those skilled in the art. They mayhe prepared, forexample,'by the procedure described by Woodward et al.in the Journal of the American Chemical Society, vol. 74, page 4241(1952). In this procedure, the steroid compound is taken up in thecarbonyl compound, for example, acetone, methyl ethyl 'ketone ordi-n-butyl ketone which has been dried over a suitable drying agent suchas anhydrous potassium carbonate. Anhydrous copper sulfate is added andthe mixture agitated for from about 24 to about 48 hours. The mixture isthen ,filtered and the desired product recovered, for example, byremoval of the solvent in vacuo. Other methods of forming acetals andketals are also applicable. For example, the steroid maybe taken ditionsalt at a temperature of fromabout 90 C. to about 140 C- for from about2 to about 24 hours in an alkanol solvent containing upto five carbonatoms. The steroid carbonate and then transformed into a quaternarycompound by reaction with an alkyl halide in accordance with 1 28,179which also claims the products. The conversion acid additionsalt isconverted'to a free base'by neutralize 0:67.67; H=7.75. Found: C=67.54;H=8.10.

tion with an acid reagent such as aqueous sodium biis effected bymaintaining the quaternary compound in an aqueous solution at a pH offrom about 7 to about 12 at a temperature of from about 20 C. to about30 C. for a period of from about 1 to about 6 hours.

The following examples are given solely for the purpose ofillustrationand are not to be construed as limitations of this invention, manyvariations of which are possible without departing from the spirit or-scope thereof.

EXAMPLE I ZI-Hydroxymethyl-A -Rregnadiene-l 15,1 70;,21 -T riol-3,20-Dione A mixture containing 1.4 g. of 21-methylene-A-pregnadiene-l118,17a diol3,20-dione (prepared as described in copendingand concurrently filed patent application Serial No. 28,179) and 1.00 g.of osmium tetroxide in SD mLIof dioxane wassallowed to stand at 25 C.for48 hours. The mixture was filtered and .thetfiltrate saturated tostand for /2 hour and filtered. The solvent was removed'in vacuo and theresidue'recrystallized twice from 1:1 ethyl acetate-methanol mixture.

A. max.-=243 mu, e= 14,700. Calculated forC H O 9 EXAMPLE n 21-Hydroxymethyl-A -Pregnne-l 1,8,1 7u,21-Triol- 3 ,ZO-Dione #A mixturecontaining equimolar quantities of osmium tetroxide and 21 methylene Apregnene-l lBJh-diol- 3,20-dione in 50 ml. of dibutyl ether was allowedto stand for 72 hours at 20 C. The mixture was filtered and the filtratesaturated with hydrogen sulfide. The hydrogen sulfide saturated filtratewas allowed to stand for 1 hour and the back precipitate removed byfiltration. The solvent was removed in vacuo to yield the desiredproduct asa residue.

EXAMPLE in 21 -H ydroxymethyl-A -Pregnatriene-I 1 5,1 741,2]

a 1 T ril-3 ,20Di0ne A mixture containing 21-methylene-A -pregnatriene-1113,17a-diol-3,20-dione together with a 20% molar excess of osmiumtetroxide in 75 ml. of tetrahydrofuran was allowed to stand at 30 C. for16 hours. The mixture was filtered and the filtratesaturated withhydrogen sulfide. The hydrogen sulfide saturated filtrate was filteredand the solvent removed in vacuo to yield the desired product as aresidue.

EXAMPLE W 7 i ethyl- 211-Hydroxymethyl-A -Pregnadiene- 11;3,1'7u,21-Tri0l-3,20-Dione A mixture containing 1.4 g. of2-methyl-21-methy1ene- A -pregnadiene-11fl,17a-diol-3,20-dione (preparedas de scribed in copending and concurrently filed patent applicationSerial No. 28,179) and 1.00 g. of osmium tetroxide.

in 50 ml. of dioxane was allowed to stand at 25 C. for 48 hours. Themixture was filtered and the filtrate saturated with hydrogen sulfide.The saturated filtrate was allowed to stand for /2 hour and filtered.The solvent was removed in vacuo and the residue recrystallized twicefrom 1:1 ethyl acetate-methanol mixture.

EXAMPLE V A mixture containing equimolar quantities of osmium tetroxideand 6oc-flll01'0 21 methylene-A -pregnene-llfi, 17a-diol-3,20-dione in50 ml. of dibutyl ether was allowed to stand for 72 hours at 20 C. Themixture was filtered and the filtrate saturated with hydrogen sulfide.The hydrogen sulfide saturated filtrate was allowed to stand for 1 hourand the black precipitate removed by filtration. The solvent was removedin vacuo to yield the desired product as a residue.

EXAMPLE VI 16a-Methyl-21-Hydr0xymethyl-A -Pregnadiene- 11,8,1 7t,21-Triol-3,20-Di0ne A mixture containing 16u-methyI-ZI-methyIene-Apregnadiene-l lB,17a-diol-3,20-dione together with a 20% molar excess ofosmium tetroxide in 75 ml. of tetrahydrofuran was allowed to stand at 30C. for 16 hours.

The mixture was filtered and the filtrate saturated with hydrogensulfide. The hydrogen sulfide saturated filtrate was filtered and thesolvent removed in vacuo to yield the desired product as a residue.

' EXAMPLE v11 16B-Methyl-21-Hydroxymethyl-A -Pregnadiene-11,8,17a,21-Tri0l-3,20-Di0ne A mixture containing16a-methyl-21-methylene-A 10 pregnadiene-l1fi,17a-dio1-3,20-dionetogether with a 20% molar excess of osmium tetroxide in 75 ml. oftetrahydrofuran was allowed to'stand at 30 C. for 16 hours. The mixturewas filtered and the filtrate saturated with hydrogen sulfide. -Thehydrogensulfide saturated, filtrate was filtered and the solvent removedin vacuo to yield the desired product as a residue.

EXAMPLE VI-II 3,11 ,ZO-Trione 16-Acetate A mixture containing 1.4 g. of2l-methylene-A -pr'egnene-16a,17a dio1-3,20-dione 16-acetate (preparedas described in copending and concurrentlyfiled patent applica: tionSerial No. 28,179) and 1.00 guof osmium tetroxide in 50 ml. of dioxanewas allowed to stand at C. for48 hours; The mixture was filtered and thefiltrate saturated with hydrogen sulfide. The saturated filtrate wasallowed to stand for /2 hour and filtered. The solvent was removed invacuo and the residue recrystallized twice from.

1:1 ethyl acetate-methanol mixture.

The following list sets forth some of the compounds within the purviewof'this invention prepared by the procedures set forth in the foregoingexamples. The list is given to avoid unnecessary repetition ofexperimental de- 6a-fluoro-9a-chloro-21-hydroxymethyl-A -pregnene-1 1B,

60c-flll0I'0-9 a-chloro-21-hydroxymethyl-A -pregnene- 17 a,

214iiol-3,11,20-trione 6owfluoro-9m-bromo-21-hydroxymethyl-A-pregnene-17a,

21-diol-3,1 1,20-trione 60L-flllO1O-9OL- brOIIlO-2 1-hydroxymethyl-A-pregnadiene- 17a,21-diol-3,1 1,20-trione 6u-fluoro-21-hydroxymethyl-A-pregnene-17a,21-diol-3, 1 1',

20-trione 6u-fiuoro-21-hydroxymethyl-A -pregnadiene-17a,2l-diol- 3,11,20-trione 6m-fluoro-21-hydroxymethyl-M-pregnadiene-11B,16a,21-

triol-3,20-dione v 6u-fluoro-21 hydroxymethyl-A -pregnadiene- 1 15,16,

21-tetrol-3,20-dione l 6m-fluoro-21-hydroxymethyl-M-pregnene-16a,17cc,2l-1;Ii01

3,11,20-trione 6 oc-flllOI'O-Z 1-hydroxymethyl-A -pregnadiene-1 15,1611,

17a,21-tetrol-3,20-dione 6oz-fluoro-21-hydroxymethyl-A -pregnadiene-16a,17a,2 1-

triol-3,1 1,20-trione 6u-methyl-9a-fluoro-21=hydroxymethy1-A-pregnadiene- 11B,17a,21-trio1-3,20-dione6pt-methyl-9or-bromo-21-hydroxymethyl-A -pregnadiene- 11fl,17oz,21-tri01-3,20-di0ne zt-hy vex meth rm re uadtenefma,mandrel-3,;1,

A variety of mono-, diand trieste rs of the foregoing ozand B-propanoylcompounds, including the 16-hydroxylated compounds, were prepared inaccordance with standard methods. These include. the acetates,propanoates, propenoa'tes, octanoates; ben'zoates, eycl'ohexanoates,decanoates, butenoates; hemiglutarates and hemisuccinates' l'n 'the caseof acid esters, -'thecompounds were conyerted to metal or" alkalineearth metal salts byreaction-with-a suitable base'sueh as sodium orbariumhydroxide.

(Compounds within the-purviewof this invention havinganl'l-keto-substituent are prepared by oxidation of the corresponding l-lhyd'rox-ylated"compounds or by using 11- keto compounds as startingmaterials; In the event that the final-product is tohbe oxidized, it isbest 'to protect P m-BA roN on-acntmLs AND KETALS The following exampleis illustrative. of two of. the:

methods which are. used to prepare the carbonyl derivatives ofinyention,including those. prepared. from the ompoundsof the. previous. examplesrThose prepared by these methods include. the. Iacetal'sj and. ketals.fi'om: acetaldehyde, propionaidehyde butyraldehyde,. acetone,di-isopropyl ketone, methyl ethyl ketone and di-n-butyl ketone.

21 hydroxymethyl A pregnadiene 11fl,l7u,2ltrio1-3', 2.0=dione;. (1100;mg.' was; taken-up'in IOU-m1. of acetone which had been-previously driedover anhydrous potassium carbonate. To this mixture there was added: 495ing; o'fanhydrous copper'sulfate and the mixture. was .stirredat roomtemperature for two days; The: mixture? was: filtered, dried overanhydrous potassium carbonate, again filtered and the excess solventremovedin vacuo. Theresidue was tritur-ated with ether containinga fewdrops of acetone; and thedesired product recovered byfiltration.

9oz fluoro 21 hydroxymethyl A pregnadiene (350 mg.) 'was taken up in 25ml. of propionaldehyde containing two drops of concentrated hydrochloricacid. The mixture was;refluxed-{0 5minutesand allowed to stand at roomtemperature for eight'hours, The desired product was precipitated by.the addition of water and isolated'by'filtration. '7 i What is claimedis:

m m O m m H t m 00R 0 O H 4 H H n s s ne s g c o c o R t s X 5 x, a Y Wm A v v Aw V R O 5 m H m 0% n s m c 7 8 v R R vm. a v w. R H 4 C m m io\ /0 H m m k n Ln 3 m C c c o x m X, i :1 D m d z 3 m a Y m mm mm AIV ou dt 1 0 mm B mat mm c w m 1% s m and and

(ilHORu R R and R are selected from the group consisting 03 of hydrogenand acyl groups containing only carbon, hy-

Y drogen and oxygen and derived from 'mono and di- X carboxylic acidscontaining up to ten carbon atoms; X CH3,"

is selected from the group consisting of hydrogen, halogen, methoxy andethoxy; Y is selected from the group consisting of B-hydroxyl and keto;and R and R are selected from the group consisting of hydrogen and loweralkyl each containing up to four carbon atoms, at least one of R and Rbeing alkyl in a particular compound.

8,08%,74-7 15 16 V p w 2. A pharmaceutical composition comprising a com-20 C. to abont 30 C. for a period of from about 16 to pound as claimedin claim 1 together with a pharmaceuti- 'a'bo nt 72"hours'" anddecomposing resulting osmate ester cally acceptable carrier. by reactionwith hydrogen sulfide;

3. In a process for the preparation of a compound as claimed in claim 1the steps which comprise contacting 5- Referencesccifed in the file ofthis P the corresponding l7i3-propenoy1 compound with osmip um tetroxidein a lower ether solvent containing'up UNITED-STATES PATENTS to eightcarbon atoms at a tempei-ature of from about 2,389,325 Reichstein Nov.20, 1945

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE HAVING THEFORMULAE: